1. Field of the Invention
The invention relates to a method for ductal tube tracking imaging for breast cancer detection and imaging, to an apparatus for ductal tube tracking, and to products comprising a computer readable medium comprising programs that includes displaying ductal tube images.
2. Prior Art
The two leading methods for screening the female population and detect breast cancer are currently high-quality X-ray mammography and breast ultrasound. The sensitivity of mammography has been estimated to be 63-88% and is lower by 10% or more for women aged 40-49 years and in older women using hormonal replacement therapy (HRT) than it is for other older women (Laya M B, Larson E B, Taplin S H, et al.: Effect of estrogen replacement therapy on the specificity and sensitivity of screening mammography. Journal of the National Cancer Institute 88(10): 643-649, 1996; and Persson I, Thurfjell E, Holmberg L: Effect of estrogen and estrogen-progestin replacement regimens on mammographic breast parenchymal density. Journal of Clinical Oncology 15(10): 3201-3207, 1997). Efforts to improve mammography focus on developing and applying digital mammography, however, X-ray mammography suffers from several limitations in addition to the use of ionizing radiation (albeit at low dose).
Ultrasound has NO hazard radiation exposure, however, it is used as an adjunct method to mammography and not for routine breast cancer screening because it does not consistently detect certain early signs of cancer.
Breast MRI studies were first applied in the 1980s and were based on the contrast provided by T1 and T2 nuclear relaxation processes of the tissue water (Yousef S J E, Duchesneau R H, Alfidi RJ, et al. Magnetic resonance imaging of the breast. Radiology 150: 761-6, 1984; Partain C L, Kulkarni M V, Price R R, et al. Magnetic resonance imaging of the breast: functional T1 and three-dimensional imaging. Cardiovasc Intervent Radiol 8: 292-9, 1986; and Santyr G E. MR imaging of the breast. Magn Res Imag Clin North Am 2: 673-90, 1994). The contrast achieved by these mechanisms was not sufficient for discriminating between the normal fibroglandular tissue and breast lesions (benign and malignant), except for T2 contrast that clearly identified fluid cysts.
Subsequent studies of contrast enhanced MRI using gadolinium based contrast agents, demonstrated the capability to sharply delineate breast lesions. Currently, the standard protocol for breast cancer detection by MRI is based on dynamic contrast-enhanced (DCE) MRI, originally suggested by Kaiser and Zeitler (Kaiser W A, Zeitler E. MR imaging of the breast: fast imaging sequences with and without Gd-DTPA. Preliminary observations. Radiology 170: 681-686, 1989).
The applicant and co-workers have been involved for the last 15 years in investigating the pathophysiological basis of DCE-MRI in breast cancer animal models and in humans, developing new protocols and image processing algorithms for improving breast cancer diagnosis, see                i. Furman-Haran E, Margalit R, Grobgeld D and Degani H, “Dynamic Contrast Enhanced Magnetic Resonance Imaging Reveals Stress Induced Angiogenesis in MCF7 Human Breast Tumors” Proc. Natl. Acad. Sci. USA, 93: 6247-6251, 1996.        ii. Degani H, Gusis V, Weinstein D, Fields S, Strano S. Mapping pathophysiological features of breast tumors by MRI at high spatial resolution. Nat Med. 3(7): 780-2, 1997.        iii. Furman Haran E, Grobgeld D, and Degani H, Dynamic Contrast Enhanced Imaging and Analysis at High Spatial resolution of MCF7 Human breast Tumors J. Magn. Reson. 128: 161-171, 1997.        iv. Furman-Haran E, Grobgeld D, Degani H, Decreased cellular volume fraction and increased microvascular permeability indicate response of MCF7 xenografts to tamoxifen; application of the 3 time point contrast enhanced MRI method, Clinical Cancer Research, 4: 2299-2304, 1998.        v. Weinstein D, Strano S, Cohen P, Fields S, Gomori J M, Degani H. Breast fibroadenoma: mapping of pathophysiologic features with three-time-point, contrast-enhanced MR imaging—pilot study. Radiology. 210(1): 233-40, 1999.        vi. Furman-Haran E, Grobgeld D, Kelcz F, Degani H. Critical role of spatial resolution in dynamic contrast-enhanced breast MRI. J Magn Reson Imaging. 13(6): 862-7, 2001.        vii. Kelcz F, Furman-Haran E, Grobgeld D, Degani H. Clinical testing of high-spatial-resolution parametric contrast-enhanced MR imaging of the breast. AJR Am J. Roentgenol. 179(6): 1485-92, 2002.        viii. Furman-Haran E, Schechtman E, Kelcz F; Kirshenbaum K, and Degani H. MRI Reveals Functional Diversity of the Vasculature in Benign and Malignant Breast Lesions. Cancer, 15; 104(4): 708-18, 2005.        ix. Eyal E, Furman-Haran F, Badikhi D, Kelcz F, and Degani H. Combination of model-free and model-based analysis of dynamic contrast enhanced MRI for breast cancer diagnosis Proc. SPIE Vol. 6916, 69161 B, Mar. 12, 2008.        x. Eyal E, Degani H. Model-based and model-free parametric analysis of breast dynamic-contrast-enhanced MRI. NMR Biomed, 22(1): 40-53, 2009.        
Despite the very high sensitivity of DCE-MRI, this procedure is not used for routine breast cancer screening, most likely because of its relatively high costs and significant false positive rates (which varies between different centers due to lack of standardization). In addition, as gadolinium-based contrast agents may trigger the development of nephrogenic systemic fibrosis (NSF) in patients with renal failure (Grobner T, Gadolinium—a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant 21: 1104-108, 2006), the accumulated risk of gadolinium based contrast agents to induce NSF presents a limitation in using it for breast cancer screening (Thomsen HS, Marckmann P, Logager VB 9: Update on nephrogenic systemic fibrosis Magn Reson Imaging Clin N Am. 16(4): 551-60, vii 2008; and Broome DR. Nephrogenic systemic fibrosis associated with gadolinium based contrast agents: a summary of the medical literature reporting. Eur J Radiol. 66(2):230-4, 2008).
More recently a new MRI approach based on contrast provided by the self diffusion of water in tissues, or through parameterization of the apparent diffusion coefficient (ADC) has been proposed for the detection of breast cancer. Applicants have previously investigated the extracellular and intracellular diffusion characteristics in the different micro-environments of human breast cancers implanted in nude mice. Due to the high cell density in proliferating cancer regions, the cancer tissue exhibited a lower ADC in the extracellular compartment (median value of 1.0×10−3 mm2/s×10−3) as compared to water ADC, similar to the values found in breast cancer patients, whereas the intracellular ADC was further lower by one order of magnitude as a result of the more complex intracellular milieu and the restriction by the cells' membrane. The clinical studies showed significant differences between the mean ADC of cancers, benign lesions and normal breast tissue, however, a large overlap was exhibited between the individual ADC values of the various normal and abnormal breast tissue. It has been thus concluded that mapping the apparent diffusion coefficients may provide an adjunct method to the common contrast enhanced MRI method for breast cancer diagnosis.
It is well established that mammary malignancies originate in the epithelial tissues of the ducts, and spread along ducts. Even when the cells are invasive and outgrow the ducts, the ductal spread will still be extensive. Consequently, the ductal structures are an imperative area of investigation of malignant breast transformation.
Current knowledge of the structural features of the ductal system was initially discovered by Sir Astley Cooper in 1840 by duct injection studies in women who died during lactation. In this studies it was revealed that human breast tissue is organized into separate lobes, each composed of one central duct, its peripheral branches and their associated glandular tissues. This architecture is very challenging to study in its entirety: whole-breast ductal trees mapping has only been achieved for two ex vivo human breasts and on two anatomical studies of breast mastectomy specimens (Moffat D F, Going J J, Three dimensional anatomy of complete duct systems in human breast: pathological and developmental implications. J Clin Pathol 49:48-52, 1996; and Ohtake T, Kimijima I, Fukushima T, Yasuda M, Sekikawa K, Takenoshita S, Abe R: Computer-assisted complete three dimensional reconstruction of the mammary ductal/lobular systems: implications of ductal anastomoses for breast-conserving surgery. Cancer 91: 2263-2272, 2001). Moffat and Going reported 3D computer model based on sub-macroscopic coronal slices of an autopsy breast. Ohtake et al applied computer simulations based on surgical quadrantectomies to analyze ductal anatomy. Increasing interest in the intraductal approach for breast cancer treatment led Love and Barsky (Love S M, Barsky S H, Anatomy of the nipple and breast ducts revisited. Cancer, 101: 1947-1957, 2004) to review a large series of ductograms showing that more than 90% of all nipples examined contained 5-9 ductal orifices, generally arranged as a central group and a peripheral group. Each nipple orifices communicated with a separate non-anastomosing ductal system, which extended to the terminal duct lobular unit. Going and Moffat (Going J J, Moffat D F, Escaping from Flatland: clinical and biological aspects of human mammary duct anatomy in three dimensions. J Pathol 2004: 203:538-544) investigated the number of milk collecting ducts in excised nipples, and the 3D structure of the collecting ducts, as well as the volume of all duct trees (lobes). Their results indicated three distinct nipple duct populations with diversity in the number of nipple central ducts and in the volumes of the lobes. Overall, however, these independent studies were contradictory in the number of ductal orifices, the number of different ductal trees and the presence of anastomoses among different ductal trees.
None of the available imaging methods employed today has succeeded in tracking the entire ductal system of the breast in vivo, although this significant challenge has been realized, and initial ultrasound studies of the lactating breast (Ramsay D T, Kent J C, Hartmann R A, Hartmann P E: Anatomy of the lactating human breast redefined with ultrasound imaging. J Anatomy 206: 525-534, 2005), as well as detection of sectional ductal structures using second-order shape measurements were performed (Gooding M J, Mellor m, Shipley J A, Broadbent K A, Goddard D A, Automatic mammary duct detection in 3D ultrasound, Med Image Compute Assist Intern Into Conf Med Image Compute Compute Intersv 8: 43441, 2005). The ability to measure water self diffusion by MRI and to track anisotropic water movement has been known for decades (Gooding M J, Mellor m, Shipley J A, Broadbent K A, Goddard D A, Automatic mammary duct detection in 3D ultrasound, Med Image Compute Assist Intern Into Conf Med Image Compute Compute Intersv 8: 43441, 2005; and Stejskal E O, and Tanner J E, Spin diffusion measurements: spin echoes in the presence of a time dependent field gradient, J Chem Phys 42: 288-292, 1965), and it was successfully applied for tracking fibers in the brain, as well as helping diagnose a range of brain abnormalities.